Biomedical subjects

Manuel Llinás

Publications and source records attributed to Manuel Llinás.

5 recordsLinked to original sources

PubMed2006

Comparative whole genome transcriptome analysis of three Plasmodium falciparum strains.

Gene expression patterns have been demonstrated to be highly variable between similar cell types, for example lab strains and wild strains of Saccharomyces cerevisiae cultured under identical growth conditions exhibit a wide range of expression differences. We have used a genome-wide approach to characterize transcriptional differences between strains of Plasmodium falciparum by characterizing the transcriptome of the 48 h intraerythrocytic developmental cycle (IDC) for two strains, 3D7 and Dd2 and compared these results to our prior work using the HB3 strain. These three strains originate from geographically diverse locations and possess distinct drug sensitivity phenotypes. Our goal was to identify transcriptional differences related to phenotypic properties of these strains including immune evasion and drug sensitivity. We find that the highly streamlined transcriptome is remarkably well conserved among all three strains, and differences in gene expression occur mainly in genes coding for surface antigens involved in parasite-host interactions. Our analysis also detects several transcripts that are unique to individual strains as well as identifying large chromosomal deletions and highly polymorphic regions across strains. The majority of these genes are uncharacterized and have no homology to other species. These tractable transcriptional differences provide important phenotypes for these otherwise highly related strains of Plasmodium.

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PubMed2005

Mining the malaria transcriptome.

Malaria remains the most devastating parasitic disease worldwide, and is responsible each year for >500 million infections and between one million and two million deaths of children under five years of age. Plasmodium falciparum is the most prevalent and deadly malaria parasite of humans, and a huge amount of data about it is now publicly available following completion of its genome sequence, the complete transcriptome of its asexual blood stages and proteomic analyses of its different life stages. Thus, new computational approaches are needed to analyze these data to yield biologically meaningful results that can be validated experimentally and, hopefully, lead to alternative control strategies. In this article, we highlight the importance of new computational approaches in mining the malaria transcriptome of the intraerythrocytic developmental cycle of P. falciparum.

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PubMed2004

Genomic dissection of the cell-type-specification circuit in Saccharomyces cerevisiae.

The budding yeast Saccharomyces cerevisiae has three cell types (a cells, alpha cells, and a/alpha cells), each of which is specified by a unique combination of transcriptional regulators. This transcriptional circuit has served as an important model for understanding basic features of the combinatorial control of transcription and the specification of cell type. Here, using genome-wide chromatin immunoprecipitation, transcriptional profiling, and phylogenetic comparisons, we describe the complete cell-type-specification circuit for S. cerevisiae. We believe this work represents a complete description of cell-type specification in a eukaryote.

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PubMed2004

Pernicious plans revealed: Plasmodium falciparum genome wide expression analysis.

The asexual intraerythrocytic developmental cycle (IDC) of Plasmodium falciparum is responsible for the majority of the clinical manifestations of malaria in humans. Although malaria has been studied for over a century, the elucidation of the full genome sequence of P. falciparum has now allowed for in-depth studies of gene expression throughout the entire intraerythrocytic stage. As the mainstays of anti-malarial chemotherapy become increasingly ineffective, we need a deeper understanding of fundamental plasmodial bioregulatory mechanisms to successfully subvert them. Recent gene expression studies have begun to examine different aspects of the IDC and are providing key insights into the basic mechanisms of Plasmodium gene regulation and are helping to define gene functions. However, to date, no transcription factor has been fully characterized from Plasmodium and the definitive identification of cis-acting regulatory elements along with their corresponding trans-acting partners is still lacking. The characterization of the transcriptome of P. falciparum is the first major step towards the understanding of the genome wide regulation of gene expression in this parasite. IDC expression data for almost every gene in the P. falciparum genome can now be publicly queried at and. The results of these studies suggest promising leads for identifying novel targets for anti-malarial therapeutics and vaccines in addition to providing a solid foundation for the ongoing elucidation of plasmodial gene expression.

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PubMed2003

The transcriptome of the intraerythrocytic developmental cycle of Plasmodium falciparum.

Plasmodium falciparum is the causative agent of the most burdensome form of human malaria, affecting 200-300 million individuals per year worldwide. The recently sequenced genome of P. falciparum revealed over 5,400 genes, of which 60% encode proteins of unknown function. Insights into the biochemical function and regulation of these genes will provide the foundation for future drug and vaccine development efforts toward eradication of this disease. By analyzing the complete asexual intraerythrocytic developmental cycle (IDC) transcriptome of the HB3 strain of P. falciparum, we demonstrate that at least 60% of the genome is transcriptionally active during this stage. Our data demonstrate that this parasite has evolved an extremely specialized mode of transcriptional regulation that produces a continuous cascade of gene expression, beginning with genes corresponding to general cellular processes, such as protein synthesis, and ending with Plasmodium-specific functionalities, such as genes involved in erythrocyte invasion. The data reveal that genes contiguous along the chromosomes are rarely coregulated, while transcription from the plastid genome is highly coregulated and likely polycistronic. Comparative genomic hybridization between HB3 and the reference genome strain (3D7) was used to distinguish between genes not expressed during the IDC and genes not detected because of possible sequence variations. Genomic differences between these strains were found almost exclusively in the highly antigenic subtelomeric regions of chromosomes. The simple cascade of gene regulation that directs the asexual development of P. falciparum is unprecedented in eukaryotic biology. The transcriptome of the IDC resembles a "just-in-time" manufacturing process whereby induction of any given gene occurs once per cycle and only at a time when it is required. These data provide to our knowledge the first comprehensive view of the timing of transcription throughout the intraerythrocytic development of P. falciparum and provide a resource for the identification of new chemotherapeutic and vaccine candidates.

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